Selective PPARδ Modulators Improve Mitochondrial Function:Potential Treatment for Duchenne Muscular Dystrophy (DMD)Bharat Lagu,*,† Arthur F. Kluge,† Effie Tozzo,† Ross Fredenburg,† Eric L. Bell,†

Matthew M. Goddeeris,† Peter Dwyer,† Andrew Basinski,† Ramesh S. Senaiar,‡ Mahaboobi Jaleel,‡

Nirbhay Kumar Tiwari,‡ Sunil K. Panigrahi,‡ Narasimha Rao Krishnamurthy,‡ Taisuke Takahashi,§

and Michael A. Patane†

†Mitobridge, Inc. (a wholly owned subsidiary of Astellas Pharma.), 1030 Massachusetts Avenue, Cambridge, Massachusetts 02138,United States‡Aurigene Discovery Technologies, Ltd., Bengaluru and Hyderabad, India§Astellas Pharma., Tsukuba, Japan

*S Supporting Information

ABSTRACT: The X-ray structure of the previously reported PPARδ modulator 1 bound to the ligand binding domain (LBD)revealed that the amide moiety in 1 exists in the thermodynamically disfavored cis-amide orientation. Isosteric replacementof the cis-amide with five-membered heterocycles led to the identification of imidazole 17 (MA-0204), a potent, selec-tive PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested in vivo in mice and in vitro in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); 17 altered the expression of PPARδtarget genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMDpatients.

KEYWORDS: PPARδ modulators, Duchenne Muscular Dystrophy (DMD), mdx mouse, imidazoles, cis-amide

Duchenne Muscular Dystrophy (DMD) is an X-linkedrecessive genetic disease involving severe muscle wastingthat results from cycles of muscle degeneration/regeneration.1,2

DMD patients carry mutations in the DMD gene, whichencodes for dystrophin, a cellular protein scaffold that is criticalfor muscle membrane integrity.3 In addition to weakenedstructural integrity, DMD is also characterized by mitochondrialimpairment with evidence of decreased fatty acid oxidativephosphorylation.4−7

In skeletal muscle, PPARδ elicits a transcriptional cascaderesulting in increased fatty acid oxidation while sparing glu-cose utilization, which enables muscle to function for a lon-ger duration without decreasing systemic glucose levels orincreasing muscle lactic acid.8 We hypothesized that engagingthe PPARδ transcriptional cascade with a selective PPARδmodulator would provide functional improvements to DMDmuscle.

The selectivity for PPARδ is considered to be crucial tomitigate the undesirable effects (such as hepatotoxicity,myopathy, edema, cardiac toxicity, etc.) observed with somemodulators of PPARα (fibrates), PPARγ (thiazolidinediones),and dual PPARα/γ (e.g., Muraglitazar) in clinical and/orpreclinical studies,9,10 while GW501516,11 a known PPARδmodulator, has shown tumorogenic effects in mice.12 As per thecompany Web sites, two modulators of PPARδ, Seladelpar andElafibranor, have cleared the two-year carcinogenicity studies inrats. This suggests that tumorogenic potential is not a class effectfor the PPAR modulators.We recently disclosed the potent and selective PPARδ

modulator 1 (Figure 1), which displayed significantly improved

Received: June 23, 2018Accepted: July 31, 2018Published: July 31, 2018

Letter

pubs.acs.org/acsmedchemlettCite This: ACS Med. Chem. Lett. 2018, 9, 935−940

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pharmacokinetic properties relative to previously reportedcompounds.13−15 The X-ray structure of 1 bound to the ligandbinding domain (LBD) of the PPARδ receptor revealed that thecarbonyl oxygen and the N-methyl group are in a cis relation-ship.13 A trans-amide has been reported to be thermodynami-cally favored over a cis-amide.16 cis-Amides are uncommon even inthe peptide literature, especially for amino acids other thanproline.17 Molecular mechanics-based energy minimization andconformational analysis of 1 predicted that the trans isomeris favored by 1.3 kcal/mol over the cis isomer.18 Therefore, wereasoned that a molecule in a “locked cis-amide” conformationwould improve binding affinity for PPARδ. Herein, we disclose aseries of compounds represented by general structure 2, wherefive-membered heterocyclic rings (Figure 1) serve as isostericreplacements of the cis-amide bond.The heterocyclic cores required for compounds 2a−g were

synthesized using known synthetic procedures (see SupportingInformation for the detailed procedures). Synthesis of 2g isshown in Scheme 1 as a representative example.PPARδ, PPARα, and PPARγ activities of these compounds

were assessed using transactivation assays.19 All the compoundswere screened for exposure in mice following an intravenousdose of 3 mg/kg. The results are shown in Table 1.All of the heterocyclic compounds (except compound 2f)

in Table 1 show greater affinity (EC50 1000-fold less potent for PPARα and PPARγreceptors). Unlike compound 1, all the compounds (except 2b)shown in Table 1 have plasma clearances that exceed hepaticblood flow in mice (>85 mL/min/kg), short half-lives (

for 13, even though the Val312 conformation is conservedin both structures. This movement is possibly necessitatedby the presence of the benzyl moiety on the imidazole ring.Ile328 in PPARδ is replaced by methionine residues in PPARαand PPARγ. Changes in the Ile328 region and the water-mediated interaction with Leu304 potentially contribute tothe improved PPARδ selectivity for the imidazole series ofcompounds.Compound 17 was profiled in multiple in vitro and in vivo

assays (Table 3). Compound 17 is >10 000-fold selective foractivation of PPARδ over PPARα and PPARγ receptors. ThePPARδ potency was 10-fold less for mouse and rat PPARδreceptors than for the human PPARδ receptor; this effect is welldocumented for PPAR modulators.11 Compound 17 is selective(EC50 >10 μM) over other nuclear receptors, for example:

androgen, progesterone, and glucocorticoid receptors. Com-pound 17 is also inactive in a panel of 68 receptors andtransporters that are known to pose safety-related challenges inthe clinic. Compound 17 exhibits high protein binding to mouseplasma, good permeability, and low potential for efflux.Compound 17 did not show mutagenic potential or inhibitmajor cytochrome P450 enzymes (IC50 ≥10 μM). Compound17 has acceptable PK profiles in mice and rats upon oraldosing.23 In the aggregate, these properties made 17 (MA-0204)an excellent candidate for study in pharmacological assays.For compound 17 (MA-0204) to be considered as a potential

treatment for Duchene Muscular Dystrophy (DMD), it wasnecessary to demonstrate that it met at least three criteria:(1) elicit a response in the target tissue, i.e., skeletal muscle,(2) affect changes in the PPARδ-responsive genes in DMDpatient myoblasts, and (3) affect beta oxidation of fatty acid inpatient myoblasts. The results from these in vivo and ex vivoexperiments are described below.To determine if 17 was capable of eliciting a biological effect

in skeletal muscle, mice were dosed orally with MA-0204 andGW501516, and target gene expression was assessed by qPCR(quantitative polymerase chain reaction). As shown in Figure 3,17 increased PPARδ target gene transcription in the muscle,represented here by Pdk4 (pyruvate dehydrogenase kinase 4).In order to test for changes in fatty acid oxidation, primary

myoblasts isolated from a 17-month-old DMD patient wereutilized. Compound 17 increased PPARδ target genesANGPTL4 (angiopoietin like protein 4), CPT1a (carnitinepalmytoyltransferase 1a), and PDK4 in a dose-dependentmanner (Figure 4). Furthermore, oxidation of the long-chainfatty acid palmitic acid was significantly elevated at theconcentrations of 1.2, 4, and 12 nM (3-, 10-, and 30-foldEC50, respectively), which represents a functional improvementof up to 52% in palmitate utilization (Figure 5).In summary, we have reported the design and synthesis of a

series of potent and selective PPARδ modulators by utilizingX-ray crystallographic information derived from previouslydisclosed compounds. The key compound to emerge from thesestudies, 17 (MA-0204), combined potency and PK properties,which enabled the demonstration that selective PPARδ

Table 1. Structure−Activity Relationship in the Five-Membered Heterocyclic Series

Cpd PPARδ EC50 (nM)a PPARα EC50 (nM)

a,b t1/2 (h)c CL (mL/min/kg)c AUC (ng·h/mL)c

1 37 ± 5 6100 2.3 15 33002a 1.5 5840 0.2 180 2802b 9.5 ± 0.5 7250 0.8 55 9002c 1.3 ± 0.5 412 ± 7.1 0.8 300 1702d 1.2 13100 0.4 130 3802e 8.4 ± 1.4 16800 0.2 225 2202f 59 ± 3.6 ND 0.7 720 702g 1.0 ± 0.0 1230 ± 165 0.5 160 300

aTransactivation assay.19 In selected cases, compounds were also assayed in a protein interaction assay.20 Both assays were in good agreement.EC50 values are an average of at least two experiments (SEM shown unless single determination).

bAll the compounds, except 2d, showedEC50 >10 000 nM for PPARγ; PPARγ EC50 for 2d = 5530 nM;

cExposure data for compounds dosed i.v. at 3 mg/kg to CD-1 mice; ND = notdetermined.

Scheme 2. General Synthesis of Compounds 13−22a

aReagents and conditions: (a) prop-2-yn-1-amine, EDCI·HCl, HOBt,Et3N, DMF, RT; (b) (2-methoxyphenyl)methanamine, Zn(OTf)2,toluene, microwave irradiation, 140 °C; (c) BBr3, DCM, RT; (d) forcompounds 13−15: furan-2-boronic acid, Pd(PPh3)4, Na2CO3, DME,EtOH, H2O, 90 °C; (e) R-Br (11a or 11b or 11c), K2CO3, DMF,65 °C; (f) LiOH.H2O, THF, EtOH, H2O, RT.

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Table 2. Hexanoic Acid Region Modifications, PPAR Activity, and Selected Pharmacokinetic Data

Cpd R1 hexanoic acid region modifications PPARδ EC50 (nM)a PPARα EC50 (nM)

a t1/2 (h)b CL (mL/min/kg)b AUC (ng·h/mL)b

1 37 ± 5 6100 2.3 15 33002g 4-(2-furyl) A 1.0 ± 0.0 1230 ± 165 0.5 160 30013 4-(2-furyl) B 0.7 ± 0.2 6970 0.3 270 18014 4-(2-furyl) C 4.5 ND 2.4 120 400

15 4-(2-furyl) D 3.7 ± 0.1 >100000 1.4 73 65016 OCF3 A 0.3 ± 0.1 2290 3.1 70 240

c

17 4-OCF3 D 0.4 ± 0.1 6900 ± 1030 3.3 25 125018 4-Cl-3-F D 0.8 ± 0.1 69000 4.3c 38c 440c

19 4-Cl D 5.5 ± 2.8 >100000 1.4c 22c 752c

20 4-Me D 20 ± 4.8 78500 ND ND ND21 4-OCHF2 D 13.5 15060 ND ND ND

22 4-F D 39.0 >100000 ND ND NDaTransactivation assay.19 In selected cases, compounds were also assayed in a protein interaction assay.20 Both assays were in good agreement.EC50 values are an average of at least two experiments (SEM shown unless single determination).

bExposure data for compounds dosed i.v.at 3 mg/kg to CD-1 mice. cExposure data for compounds dosed i.v. at 1 mg/kg to CD-1 mice. ND = not determined. All the compounds showedEC50 >10000 nM for PPARγ.

Figure 2. Superposition of the X-ray structures of compound 1(magenta) and compound 13 (cyan) bound to the ligand bindingdomain (LBD) of PPARδ receptor.

Table 3. Potency, Selectivity, ADME, DMPK, PK, and Safety Data for 17 (MA-0204)

assay results

human PPARδ EC50 = 0.4 nMa

human PPARα and PPARγ EC50 = 6990 ± 1030 nM and >100 000 nM, respectivelya

mouse PPARδ and Rat PPARδ EC50 = 7.9 nM and 10 nMb

selectivity no activity in Eurofins PanLabs Lead Profiling Screen of 68 molecular targets up to 10 μM. No activity(up to 10 μM) for androgen, progesterone, and glucocorticoid receptorsc

% plasma protein binding: mouse/rat/human = 99.5/99.6/99.9

Caco-2 permeability (cm/s, ×10−6) A to B = 36; B to A = 41 (efflux ratio 1.2)

CYP450 inhibition >10 μM for CYPs except 2C9 (56% inhibition @ 10 μM)

mutagenicity nonmutagenic in mini-Ames test

mouse PKd 1 mg/kg IV: t1/2 = 2.7 h; CL = 33 mL/min/kg; Vss = 5.8 L/kg; AUC = 503 ng·h/mL3 mg/kg PO: t1/2 = 3.4 h; Cmax = 510 ng/mL; AUC = 630 ng·h/mL; %F = 42

rat PKe 1 mg/kg IV: t1/2 = 6.1 h ; Vss = 1.8 L/kg; CL = 10 mL/min/kg; AUC = 1590 ng·h/mL3 mg/kg PO: t1/2 = 4.6 h; Cmax = 1,089 ng/mL; AUC = 4920 ng·h/mL; %F = 90

monkey PKf 3 mg/kg IV: t1/2 = 6.1 h; CL = 0.4 mL/min/kg; Vss = 3.2 L/kg ; AUC = 8400 ng·h/mL10 mg/kg PO: t1/2 = 7.3 h: Cmax = 1660 ng/mL; AUC = 3840 ng·h/mL; %F = 13

aTransactivation assay. bData from Indigo Bioscience assay. cData obtained at Aurigene Discovery Technologies Pvt. Ltd. dMale CD-1 mice(n = 3). eMale Wistar rats (n = 3). fMale cynomolgus monkeys (n = 3).

Figure 3. Compound 17 (MA-0204) engages target gene expressionafter oral administration in mice (see Supporting Information fordetails).

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modulators may offer benefits as a therapeutic strategy forDMD.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on the ACSPublications website at DOI: 10.1021/acsmedchemlett.8b00287.

Experimental procedures, HPLC and 1H NMRs, andX-ray crystallographic data (PDF)

■ AUTHOR INFORMATIONCorresponding Author*Tel: (617)401-9122. E-mail: Bharat.lagu@astellas.com.ORCIDBharat Lagu: 0000-0002-2354-3126Author ContributionsThe manuscript was written through contributions of allauthors. All authors have given approval to the final version ofthe manuscript.NotesThe authors declare the following competing financialinterest(s): The authors are current or former employees ofMitobridge, Inc., Astellas Pharma., or Aurigene DiscoveryTechnologies and may have owned or currently own shares ofthese companies.

■ ACKNOWLEDGMENTSAuthors thank B. Mallesh (Aurigene Discovery Technologies)for technical assistance.

■ ABBREVIATIONSDMSO, dimethyl sulfoxide; BBr3, boron tribromide; DCM,dichloromethane; RT, room temperature; h, hour; Pd(PPh3)4,tetrakis(triphenylphosphine)palladium(0); Na2CO3, sodium

carbonate; DME, 1,2-dimethoxyethane; EtOH, ethyl alcohol;LiOH·H2O, lithium hydroxide monohydrate; THF, tetrahy-drofuran; EDCI·HCl, ethylcarbodiimide hydrochloride; HOBt,1-hydroxy benzotriazole; Et3N, triethylamine; DMF, N,N-dimethylformamide; Zn(OTf)2, zinc trifluoromethanesulfonate

■ REFERENCES(1) Bushby, K.; Finkel, R.; Birnkrant, D. J.; Case, L. E.; Clemens, P. R.;Cripe, L.; Kaul, A.; Kinnett, K.; McDonald, C.; Pandya, S.; Poysky, J.;Shapiro, F.; Tomezsko, J.; Constantin, C. Diagnosis and managementof Duchenne muscular dystrophy, part 1: diagnosis, and pharmaco-logical and psychosocial management. Lancet Neurol. 2010, 9 (1), 77−93.(2) Chelly, J.; Kaplan, J. C.; Maire, P.; Gauton, S.; Kahn, A.Transcription of the dystrophin gene in human muscle and non-muscletissues. Nature 1988, 333, 858.(3) Ryder, S.; Leadley, R. M.; Armstrong, N.; Westwood, M.; de Kock,S.; Butt, T.; Jain, M.; Kleijnen, J. The burden, epidemiology, costs andtreatment for Duchenne muscular dystrophy: an evidence review.Orphanet J. Rare Dis. 2017, 12 (1), 79.(4) Timpani, C. A.; Hayes, A.; Rybalka, E. Revisiting the dystrophin-ATP connection: How half a century of research still implicatesmitochondrial dysfunction in Duchenne Muscular Dystrophy aetiol-ogy. Med. Hypotheses 2015, 85 (6), 1021−33.(5) Carroll, J. E.; Norris, B. J.; Brooke, M. H. Defective [U-14 C]palmitic acid oxidation in Duchenne muscular dystrophy. Neurology1985, 35 (1), 96−7.(6) Khairallah, M.; Khairallah, R.; Young, M. E.; Dyck, J. R.; Petrof, B.J.; Des Rosiers, C. Metabolic and signaling alterations in dystrophin-deficient hearts precede overt cardiomyopathy. J. Mol. Cell. Cardiol.2007, 43 (2), 119−29.(7) Lin, C. H.; Hudson, A. J.; Strickland, K. P. Fatty acid oxidation byskeletal musclemitochondria in Duchennemuscular dystrophy. Life Sci.1972, 11 (7), 355−62.(8) Fan, W.; Waizenegger, W.; Lin, C. S.; Sorrentino, V.; He, M. X.;Wall, C. E.; Li, H.; Liddle, C.; Yu, R. T.; Atkins, A. R.; Auwerx, J.;Downes, M.; Evans, R. M. PPARdelta Promotes Running Endurance byPreserving Glucose. Cell Metab. 2017, 25 (5), 1186−1193.(9) Peraza, M. A.; Burdick, A. D.; Marin, H. E.; Gonzalez, F. J.; Peters,J. M. The Toxicology of Ligands for Peroxisome Proliferator-ActivatedReceptors (PPAR). Toxicol. Sci. 2006, 90, 269.(10) Nissen, S. E.; Wolski, K.; Topol, E. J. Effect of Muraglitazar ondeath and major adversecardiovascular events in patients with type-2diabetes mellitus. JAMA 2005, 294 (20), 2581.(11) Sznaidman, M. L.; Haffner, C. D.; Malloney, P. R.; Fivush, A.;Chao, E.; Goreham, D.; Sierra, M. L.; LeGrummelec, C.; Xu, E. H.;Montana, V. G.; Lambert, M. H.; Willson, T. M.; Oliver, W. R.;Sternbach, D. D. Novel selective small molecule agonists forperoxisome proliferator-activated receptor delta (PPARdelta)-syn-thesis and biological activity. Bioorg. Med. Chem. Lett. 2003, 13, 1517.(12) Geiger, L. E.; Dunsford, W. S.; Lewis, D. J.; Brennan, C.; Liu, K.C.; Newsholme, S. J. Rat carcinogenicity study with GW501516, aPPAR delta agonist. 48th Annual Meeting of the Society of Toxicology2009, PS-895.(13) Lagu, B.; Kluge, A. F.; Fredenburg, R. A.; Tozzo, E.; Senaiar, R. S.;Jaleel, M.; Panigrahi, S. K.; Tiwari, N. K.; Krishnamurthi, N. R.;Takahashi, T.; Patane, M. A. Novel highly selective peroxisomeproliferator-activated receptor delta (PPARδ) modulators withpharmacokinetic properties suitable for once-daily oral dosing. Bioorg.Med. Chem. Lett. 2017, 27 (23), 5230−5234.(14) Lagu, B.; Kluge, A. F.; Goddeeris, M. M.; Tozzo, E.; Fredenburg,R. A.; Chellur, S.; Senaiar, R. S.; Jaleel, M.; Krishna Babu, R. D.; Tiwari,N. K.; Krishnamurthi, N. R.; Takahashi, T.; Patane, M. A. Highlyselective peroxisome proliferator-activated receptor delta (PPARdelta)modulator demonstrates improved safety profile compared toGW501516. Bioorg. Med. Chem. Lett. 2018, 28, 533.(15) Wu, C. C.; Baiga, T. J.; Downes, M.; La Clair, J. J.; Atkins, A. R.;Richard, S. B.; Fan, W.; Stockley-Noel, T. A.; Bowman, M. E.; Noel, J.

Figure 4. Compound 17 (MA-0204) engages target gene expression inDMD patient muscle myoblast mice (see Supporting Information fordetails).

Figure 5. Compound 17 (MA-0204) improves fatty acid oxidation inDMD patient muscle myoblast mice (see Supporting Information fordetails).

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P.; Evans, R. M. Structural basis for specific ligation of the peroxisomeproliferator-activated receptor δ. Proc. Natl. Acad. Sci. U. S. A. 2017,114, E2563.(16) Jorgensen, W. L.; Gao, J. Cis-trans energy difference for thepeptide bond in the gas phase and in aqueous solution. J. Am. Chem. Soc.1988, 110 (13), 4212−4216.(17) Weiss, M. A.; Jabs, A.; Hilgenfeld, R. H. Peptide bond revisited.Nat. Struct. Mol. Biol. 1998, 5 (8), 676.(18) Molecular mechanics based energy minimization and conforma-tional analysis study using Molsoft/MMFF force field.(19) In the transactivation assay CV-1 cells are transfected with aPPAR ligand binding domain fused to a GAL4 promoter to generate ahormone-inducible activator. A test ligand is added and activity ismeasured in a luciferase assay. See WO2016057660 for further details.(20) In the protein interaction assay the PPAR ligand complexes witha PPAR ligand binding domain fused to an inactive fragment ofgalactosidase. This complex complements another inactive galactosi-dase fragment to form an active galactosidase enzyme that is read out ina fluorescence assay. See www.discoverx.com for details.(21) Coordinates of the X-ray structure have been deposited in theProtein Data Bank (accession code PDB 5ZXI).(22) Batista, F. A. H.; Trivella, D. B. B.; Bernardes, A.; Gratieri, J.;Oliveira, P. S. L.; Figueira, A. C. M.; Webb, P.; Polikarpov, I. Structuralinsights into human peroxisome proliferator activated receptor delta(PPAR-delta) selective ligand binding. PLoS One 2012, 7, e33643.(23) All the animal experiments were carried out as per the guidelinesof the Committee for the Purpose of Control and Supervision ofExperiments on Animals (CPCSEA), Government of India andapproved by the Institutional Animal Ethics Committee (IAEC),Aurigene Discovery Technologies Ltd, Bengaluru, India.

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